SUMMARY A great unmet need exists for pain therapies that are non-addictive and/or address pain that remains intractable to treatments available currently. Opiates, the most powerful drugs to treat pain, pose serious side effects and addictive potential; on the other hand, non-steroidal anti- inflammatory drugs (NSAIDs) are often ineffective in some types of pain. There is emerging evidence to suggest that ketogenic diets may alleviate pain. A ketogenic diet is a regimen that is high in fat and low in carbohydrates, like a strict Atkins diet. The carbohydrate restriction decreases glucose metabolism and promotes use of ketone bodies as energy in tissues such as brain and spinal cord, which induces a metabolic shift in those tissues. The ketogenic diet has shown proven clinical efficacy in epilepsy, even drug-refractory epilepsy, for many decades and demonstrated basic research potential for neuroprotection in several types of acute and chronic brain injuries and neurodegenerative conditions. A number of biochemical consequences of ketogenic diets all suggest that a ketogenic diet will be effective in elevating pain thresholds and reducing inflammatory pain. Our recent work shows that a ketogenic diet can reduce inflammation and reduce sensitivity to thermal pain in male rodents. Unfortunately, little work exists on this topic in female people or rodents, who/which have different pain sensitivity and different responses to analgesics than males; in addition, these variables change across the menstrual/estrous cycle. Our central hypothesis is that ketogenic diets will alleviate pain, particularly inflammatory pain, in female rodents in an estrous cycle stage-dependent manner. The present objective is to test the effects of ketogenic diets in acute pain (nocifensive behavior regarding heat; Specific Aim 1), acute inflammatory pain (nocifensive behavior regarding intraplantar formalin; Specific Aim 2), and persistent inflammatory pain (tactile allodynia and other behaviors after intraplantar complete Freund?s adjuvant; Specific Aim 3) while monitoring estrous cycle stage and studying any effects of the ketogenic diet on characteristics of the estrous cycle itself. Testing our hypothesis in well-established animal models is feasible and may yield new therapeutic opportunities for pain relief and a new avenue for developing pain treatments that are both effective and non-addictive.